Original Article

Journal of Veterinary Dentistry

2016, Vol. 33(2) 90-96
Effects of Buprenorphine Added to ª The Author(s) 2016
Reprints and permission:
sagepub.com/journalsPermissions.nav
Bupivacaine Infraorbital Nerve Blocks on DOI: 10.1177/0898756416657232
jov.sagepub.com
Isoflurane Minimum Alveolar Concentration
Using a Model for Acute Dental/Oral Surgical
Pain in Dogs

Lindsey B. C. Snyder, DVM, MS, DACVAA, CVA1,

Christopher J. Snyder, DVM, DAVDC2, and Scott Hetzel, MS3

Abstract
Bupivacaine appears to have a duration of action longer than previously reported. Results of this study demonstrate that the
addition of buprenorphrine may enhance the analgesic duration of effect for bupivacaine regional nerve blocks. In addition, the use
of bupivacaine alone may have analgesia that exceeds 24 hours in many cases. Although not statistically significant based on sample
size, 50% of dogs receiving the bupivacaine/buprenorphine regional anesthetic block demonstrated a decreased anesthetic
requirement 48 hours postadministration when compared to 25% of dogs receiving the bupivacaine anesthetic. No adverse
cardiorespiratory effects were noted secondary to either local anesthetic treatment. Use of bupivacaine may have analgesic effects
extending greater than 24 hours (24-72) when used in regional anesthetic blocks in veterinary dental patients with acute dental
pain. The addition of buprenorphine to bupivacaine may extend the duration of analgesia (48-96 h). The limited sample size, in
addition to patient variability in response to medications, may account for the fact that no differences were detected between the
treatments administered.

Keywords
regional nerve blocks, buprenorphine, bupivacaine, minimum alveolar concentration, dental pain, animal model

Introduction Dental dolorimetry, a method of stimulation of the tooth

Adjuncts to injectable and inhalant anesthetics have been used
to produce analgesia and decrease the amount of general anes-
thetic necessary to maintain surgical planes of anesthesia.1-4
The minimum alveolar concentration (MAC) is used as a stan-
dard measure to evaluate the effect of analgesic drugs or
adjunct techniques on inhalant anesthetic requirements. The
MAC of an inhalant is defined as the minimum steady state
alveolar concentration of an inhalation anesthetic required to
prevent gross purposeful movement to a noxious stimulus in
50% of patients.5,6 Inhalant anesthetics are associated with
increasing cardiorespiratory depression with an increasing
dose; therefore, a reduction in the MAC will minimize the
cardiorespiratory effects of inhalants.1-4,7 Additionally, using
the MAC as a standard measurement, a decrease in MAC is
used to document an analgesic or anesthetic effect of drug or
adjunctive modality.5-9 It is generally accepted that a decrease
in MAC of 20% or more is considered to be of clinical sig-
nificance in patients.7 For example, in one study, the adminis-
tration of IV morphine during inhalant anesthesia has been
shown to reduce the MAC of isoflurane by 48% in dogs.4
pulp, has been used in the experimental setting to simulate
tooth pain in both dogs and cats.10 Dental dolorimetry is an
established clinical model for pain.10-13 The model has been
used in nonanesthetized dogs10 and horses11 to assess changes
in pain threshold to noxious stimulus when using a local inject-
able analgesic agent.
Disrupting transmission of the infraorbital nerve at the level
of the infraorbital foramen has been shown to produce regional
1
Anesthesiology and Pain Management, University of Wisconsin–Madison,
School of Veterinary Medicine, Madison, WI, USA
2
Dentistry and Oral Surgery, University of Wisconsin–Madison, School of
Veterinary Medicine, Madison, WI, USA
3
Department of Biostatistics and Medical Informatics, University of
Wisconsin–Madison, Madison, WI, USA
Corresponding Author:
Lindsey B.C. Snyder, Anesthesiology and Pain Management, University of
Wisconsin–Madison, School of Veterinary Medicine, 2015 Linden Drive,
Madison, WI 53706, USA.
Email: lindsey.snyder@wisc.edu
Snyder et al
anesthesia of the canine tooth in both dogs14 and cats15 and has
been proven to decrease the MAC of isoflurane in dogs.16
During noninvasive stimulation of the tooth pulp, loss of the
reflex evoked muscle action potential in the digastric muscle-
documented analgesia of the region.14,15 Analgesia has also
been documented, showing a 23% reduction in the MAC of
isoflurane in dogs when using a model for dental pain.16 Dental
procedures are one of the primary reasons for general anesthe-
sia in small animal private practice. Improving analgesia and
anesthetic safety of dental/oral surgical procedures has much
clinical relevance.
Bupivacaine is a routinely used local anesthetic in veterin-
ary dental patients, despite being off-label. The addition of
buprenorphine to bupivacaine regional blocks in veterinary
medicine has grown in popularity in recent years based on
research and clinical use in humans. The addition of buprenor-
phine to the local anesthetic used for intraoral nerve blocks in
humans with chronic conditions has been shown to provide a 3-
fold increase in the duration of postoperative analgesia.17 Per-
ipheral mu receptors have been shown to be present in condi-
tions of chronic nociception, and local administration of
opioids has been shown to provide analgesic activity.18 Com-
plete analgesia persisted for 30 hours beyond the duration pro-
vided by the local anesthetic alone in 75% of the human
patients undergoing minor oral surgery in a study evaluating
a combination of opioid and local anesthetic administered
locally.17 In patients undergoing knee or hip replacement, the
addition of buprenorphine to the bupivacaine caudal epidural
injection, the duration of analgesia was much longer (606 min
vs 126 min) and the mean 24-hour morphine consumption was
halved. 19 The addition of buprenorphine to bupivacaine
appears to significantly increase the duration of analgesia post-
operatively, thus improving patient comfort and decreasing the
need for additional analgesics. The reduction in supplemental
analgesics can limit the side effects of those analgesics. This
practice can be of particular benefit to veterinary patients
undergoing oral surgery for conditions of chronic or acute con-
ditions by providing prolonged analgesia following discharge;
however, the effectiveness of these drugs has not yet been
evaluated.
The purpose of this study was to evaluate the effectiveness
(prolongation of clinical analgesic effect) of the addition of
buprenorphine to bupivacaine for regional anesthetic blocks
using a model for acute surgical pain associated with dental
procedures. By documenting the duration of effectiveness of
regional analgesia in these patients, baseline information will
be established to allow future comparison for conditions asso-
ciated with patients having chronic pain. By demonstrating a
decrease in MAC, dose-dependent cardiorespiratory affects
will be decreased, likely making general anesthesia safer.
Materials and Methods
The experimental animal care and use protocol used in this
study was approved by the University of Wisconsin–Madison
91
School of Veterinary Medicine’s Institutional Animal Care and
Use Committee (IACUC).
Eight adult beagle dogs, 7.7 to 17.5 months old (12.8 + 4.21
months) and 7.0 to 10.4 kg (8.6 + 1.2 kg), were enrolled in the
study after determining they were of ASA status I. General
physical examination was performed, and animals were con-
sidered to be in excellent general health. Conscious oral eva-
luation was performed by a single investigator (CJS) to
determine any signs of chronic periodontal disease including
gingival recession, furcation exposure, and missing or mobile
teeth. Overall, calculus stage 0-1 and gingivitis index 0-1 was
noted on all patients during awake oral examinations.
Each dog received 2 treatments, involving multiple anes-
thetic events for each treatment, using a randomized crossover
design. Treatment one involved isoflurane MAC determination
with regional anesthesia via an infraorbital block with bupiva-
caine alone. Treatment two involved isoflurane MAC determi-
nation with regional anesthesia via an infraorbital block with
bupivacaine and buprenorphine. Prior to the first MAC deter-
mination for each treatment, an isoflurane MAC was deter-
mined with no treatment. The MAC baseline for each patient
was determined by the average of the 2 pretreatment isoflurane
MAC determinations. Thus, each animal’s individual isoflur-
ane MAC was determined in duplicate.20
Food, but not water, was withheld for a minimum of 8 hours
prior to the start of anesthesia. A 22-gauge intravenous catheter
was placed in the right cephalic vein for fluid administration
and anesthetic induction. A balanced electrolyte solution
(note 1) was administered via the IV catheter for the duration
of anesthesia at a rate of 5 mL/kg/h. Anesthesia was induced
with intravenous propofol (note 2) administered to effect (8-10
mg/kg) prior to endotracheal intubation with a cuffed endotra-
cheal tube. Animals were placed in left lateral recumbency.
Anesthesia was maintained with isoflurane (note 3) in oxygen
via an out-of-circle, agent-specific vaporizer and a circle sys-
tem. Oxygen flow rates were set at 2 L/min for anesthetic
induction and 1 L/min for the duration of anesthesia. Con-
trolled ventilation was used throughout anesthesia to maintain
an end-tidal carbon dioxide concentration of 37 to 43 mm Hg
and to provide a constant end-tidal isoflurane concentration.
Dogs were placed on a warm water–circulating, tabletop heat-
ing pad, and a forced air heating blanket was used to maintain
core body temperature between 37 C and 38 C measured via
an esophageal temperature probe.
Dogs were instrumented with a lead II electrocardiogram
monitor, a pulse oximeter (note 4), and an oscillometric blood
pressure cuff placed just proximal to the tibiotarsal joint for
indirect measurements of arterial blood pressure. A calibrated
anesthetic analyzer (note 4) was used to continuously monitor
inspired and expired gas samples to provide end-tidal concen-
trations of isoflurane (%), oxygen (%), and partial pressure of
carbon dioxide (mm Hg). Heart rate (beats/min); respiratory
rate (breaths/min); oxygen saturation (%); and systolic, diasto-
lic, and mean arterial blood pressure (mm Hg) were measured
continuously and recorded every 5 minutes throughout anesthe-
sia. Esophageal body temperature recordings were maintained
92
in normal range by supplemental warming using a warm water
circulating blanket and warm air circulating blanket. Readings
were recorded every 5 minutes. Anesthesia took place a min-
imum of 10 days following the administration of any kind of
analgesic.
Minimum Alveolar Concentration of Isoflurane
Regardless of the treatment group, the MAC of isoflurane with
no treatment was established for each dog before performing
bilateral infraorbital nerve blocks. Each dog was maintained at
an end-tidal isoflurane concentration of 1.7%, or 1.5 times the
MAC of isoflurane in dogs (1.28%),5 for 20 minutes before
applying the first noxious stimulus. A noxious stimulus was
applied in a fashion consistent with an existing model of dental
dolimetry designed to replicate oral surgical pain associated
with dental extraction. An alligator clip anode was placed on
the right maxillary canine tooth, and a platinum needle cathode
was inserted in the right maxillary canine gingiva coronal to the
mucogingival line and overlying the tooth root. Electrocon-
ducting gel was placed on the tooth extending from the alligator
clip to buccal-free gingival margin. The electrodes were con-
nected to a stimulating device (note 5) that provided the supra-
maximal stimulus used for the noxious stimulus. A previously
described 0.5 millisecond square wave pulse stimulus of 10 to
20 mA at a frequency of 0.5 Hz15 was applied to the electrodes
for 60 seconds or until gross purposeful movement was eli-
cited.8 Gross purposeful movement was defined as pawing at
the face, lifting the head, or repetitive movements of the limbs
and resulted in discontinuation of the electrical stimulus. Jaw
chattering, twitching, swallowing, nystagmus, and torticollis
were not considered gross purposeful movements but were
considered reflexive responses associated with stimulation.8
The end-tidal concentration of isoflurane was decreased by
20% if no gross purposeful movement was elicited following
1 min of stimulation. The dog was allowed to equilibrate for 15
minutes to the lower end-tidal concentration before repeat test-
ing. This process was repeated until gross purposeful move-
ment was elicited. Following a positive response, the end-tidal
concentration of isoflurane was increased by 10%, equilibra-
tion was allowed to occur, and the dog was retested. The indi-
vidual MAC value for the treatment was calculated as the mean
value of the lowest end-tidal concentration with no movement
(negative response) and the highest end-tidal concentration that
produced movement (positive response).5,6 Since each dog
underwent two treatments, the baseline MAC for each dog was
averaged between the two pretreatment MAC determinations.
Treatment Groups
Upon establishing the baseline MAC for each treatment, the
percentage of inhalant was increased, and one of two local
block treatments were administered. Each dog was randomized
as to the order with which they would receive treatments. The
syringes were not labeled and were prepared and administered
by one individual (CJS) Treatment 1, bupivacaine block alone
Journal of Veterinary Dentistry 33(2)
(MACbupiv), consisted of administration of bilateral infraorbi-
tal regional blocks consisting of 0.3 mL 0.5% bupivacaine
(note 6) þ 0.1 mL sterile saline at both locations. Treatment
2, bupivacaine plus buprenorphine (MACbupbup), consisted of
0.3 mL 0.5% bupivacaine (note 6) þ 0.1 mL (0.3 mg/mL)
buprenorphine (note 7) infraorbital regional blocks placed at
both locations. Regardless of treatment, regional anesthesia
was administered using a 3.8 cm, 25-gauge needle placed
through buccal mucosa and extended into the infraorbital canal
0.5 cm. Treatment was performed bilaterally to account for any
nerve supply crossing midline. The needle was advanced
through buccal mucosa maintaining the needle parallel with
dental arcade. The syringe was aspirated and rotated along the
long axis aspirating to verify the needle bevel was not placed
within a blood vessel. Following administration of the regional
block, digital pressure was applied to prevent leakage of the
medications. The patient was permitted to equilibrate to 1.7%
end-tidal isoflurane as described previously. Determination of
the MAC treatment was repeated as described earlier. The
individual responsible for MAC determination (LBCS) was
blinded to the treatment administered. Following determination
of the MAC treatment of day 1, the dog was allowed to recover
fully from anesthesia. MAC determination was performed on
each subsequent day for a maximum of 5 days or until the dog
returned to the baseline MAC signifying that the effect of the
local anesthetic was no longer present. Dogs were anesthetized
at approximately the same time of day every 24 hours in order
to standardize comparison for duration of anesthetic activity.
Following return to baseline MAC of the first treatment, the
dogs were allowed a 2-day washout period before beginning
the second treatment. The second phase of the experiment was
performed as described previously, using the alternate treat-
ment. The dog was permitted to equilibrate in a deep state of
general anesthesia before sequential stimulation occurred in the
fashion described earlier. Identical parameters were monitored
and identical criteria were considered indicative as positive for
waking spontaneously or in response to the stimulus. The Iden-
tical protocol was followed with daily MAC determinations
taken until the patient returned to baseline and that treatment
was considered complete.
Data are reported as mean (standard deviation), with values
of P < .05 considered significant. The effect of treatment on the
isoflurane MAC was assessed via repeated measures analysis
of variance (RM-ANOVA). Treatment, day (as numeric), and
their interaction (if significant) were fixed effects and dog was
considered a random effect. Effect of treatment on cardiore-
spiratory variables at time of shallow sleep was also assessed
with a similar RM-ANOVA model. Individual tests were
assessed with paired t tests.
Results
All 8 dogs appeared to tolerate the treatments well and recov-
ered uneventfully from anesthesia. There were no observable
negative effects of the regional anesthetic injections. The
RM-ANOVA showed no difference in MAC based on treatment
Snyder et al
Table 1. Results of Sequential MAC Assessment in Dogs Receiving Regional Bupivacaine Nerve Blocks With (MACbupbup) or Without
(MACbupiv) Buprenorphine.
MACbupiv
Number of Dogs That Had Number of Dogs That Returned Number of Dogs That had Number of Dogs That Returned
a Reduced MAC at Testing to Baseline MAC at Testing a Reduced MAC at Testing to Baseline MAC at Testing
22% MAC reduction
Day 1: Immediately 8/8 (100%)
postadministration
Day 2: 24 hours 5/8 (62.5%)
postadministration
Day 3: 48 hours 2/8 (25%)
postadministration
Day 4: 72 hours 1/8 (12.5%)
postadministration
Day 5: 96 hours 0/8 (0%)
postadministration
Abbreviations: MAC, minimum alveolar concentration; MACbupbup, bupivacaine plus buprenorphine; MACbupiv, bupivacaine block alone.
(P ¼ .775) nor by day (P ¼ .127). The baseline (no treatment)
MAC of isoflurane (MACiso) mean (SD) was found to be
1.16% (0.17%). On the day of regional block administration
(day 1), the MAC of isoflurane and bupivacaine (MACbupiv)
and the MAC of isoflurane and bupivacaine and buprenorphine
(MACbupbup) were found to be 0.91% (0.26%) and 0.95%
(0.17%), respectively. The regional blocks caused a 22% reduc-
tion in MAC for the MACbupiv treatment and a 19% reduction
in MAC for the MACbupbup treatment (Table 1).
On day 2 of MAC determinations, all 8 dogs in each treat-
ment group were tested. The MACbupiv and MACbupbup
were found to be 1.04% (0.25%) and 1.01% (0.24%), respec-
tively. Three of 8 dogs in the MACbupiv group and 2 of 8 dogs
in the MACbupbup group returned to baseline, demonstrating
that the local anesthetic wore off between initial testing and 24
hours later. The MAC determinations ceased for dogs returning
to baseline.
On day 3 of MAC determinations, 5 of 8 dogs in the MAC-
bupiv treatment and 6 of 8 dogs in the MACbupbup were
tested. The MACbupiv and MACbupbup of the tested dogs
were found to be 1.06% (0.14%) and 0.93% (0.12%), respec-
tively. Of the remaining dogs tested in each group, the regional
blocks, 48 hours after administration, caused a 9% reduction in
MAC for the MACbupiv treatment and a 21% reduction in
MAC for the MACbupbup treatment. Three of 5 dogs in the
MACbupiv group and 2 of 6 dogs in the MACbupbup group
returned to baseline, demonstrating that the regional block
wore off between 24 and 48 hours following administration for
these dogs. Testing ceased for dogs returning to baseline.
On day 4 of MAC determinations, 2 of 8 dogs in the MAC-
bupiv treatment and 4 of 8 dogs in the MACbupbup were
tested. The MACbupiv and MACbupbup of the tested dogs
were found to be 1.17% (0.19%) and 1.04% (0.09%), respec-
tively. Of the remaining dogs that were tested 72 hours follow-
ing local block administration, the MACbupiv had a 0%
reduction and the MACbupbup group demonstrated an 11%
93
MACbupbup
19% MAC reduction
0 8/8 (100%) 0
3 6/8 (75%) 2
3 4/8 (50%) 2
1 3/8 (37.5%) 1
1 2/8 (25%) 1
reduction in MAC. One of 2 dogs in the MACbupiv group and
1 of 4 dogs in the MACbupbup group returned to baseline,
showing that the regional block wore off between 48 and 72
hours following administration for these dogs. Testing ceased
for any dog that returned to their baseline MAC.
On day 5 of MAC determinations, 1 of 8 dogs in the MAC-
bupiv treatment was tested and 3 of 8 dogs in the MACbupbup
were tested, as they had still not returned to their baseline
MAC. The MACbupiv and MACbupbup of the tested dogs
were found to be 1.3% (0%) and 0.93% (0.11%), respectively.
Of the dogs remaining in both the groups, the regional blocks,
96 hours following administration, caused an 11% increase in
MAC for the MACbupiv treatment and a 21% reduction in
MAC for the MACbupbup treatment. The remaining single dog
in the MACbupiv group and 1 of 3 dogs in the MACbupbup
group returned to baseline, revealing that the regional block
wore off between 72 and 96 hours after administration for these
dogs. No testing was done after day 5 even if the treatment
MAC had not returned to baseline. Two (25%) of eight dogs in
the MACbupbup group still demonstrated a reduced MAC 96
hours following regional block placement.
For baseline MAC, MACbupiv and MACbupbup, the heart
rate, and the arterial blood pressure increased in dogs as the
end-tidal isoflurane concentration decreased. Pawing at the
face and lifting the head were the most common positive
responses to the noxious stimulus. Body temperature remained
between 37 C and 38 C throughout anesthesia, and the pulse
oximeter never dropped below 95% for the duration of anesthe-
sia in all dogs for all treatments.
Heart rate and mean arterial blood pressure were measured
throughout anesthesia, both before noxious stimulation and
after, but is reported at the lowest end-tidal isoflurane concen-
tration, where noxious stimulus did not produce gross purpose-
ful movement. The results of the heart rate RM-ANOVA
indicated that there was a slight decrease (mean [95% CI]) in
beats per min in MACbupbup group (7.8 [16.3 to 0.7],
94
P ¼ .073) and a significant linear decrease per day of 3.0
[5.9 to 0.2] beats per min (P ¼ .034). The results of the
MAP RM-ANOVA indicated that there was no difference in
baseline mm Hg by treatment (P ¼ .131); however, the changes
in MAP over time were significantly different for each treat-
ment group (P ¼ .006). The MAP for the MACbupiv group
decreased per day by 5.2 [7.9 to 2.5] mm Hg, while the
MACbupbup group decreased only 0.2 [2.4 to 1.9] mm Hg
per day.
Discussion
The present study found that the addition of buprenorphine to
regional bupivacaine anesthesia via an infraorbital nerve block
did not extend the duration of nerve blockade in a statistically
significant manner compared to regional bupivacaine anesthe-
sia alone as measured by repeated MAC determinations. The
MAC of isoflurane decreased from baseline by 22% in the
MACbupiv treatment group and by 19% in the MACbupbup
treatment group. Regional anesthesia using bupivacaine alone
or bupivacaine plus buprenorphine via an infraorbital nerve
block significantly reduced the isoflurane MAC in dogs with-
out adversely affecting cardiovascular parameters or causing
observable adverse effects.
Inhalant anesthetics are required for immobility to perform
dental cleanings on veterinary patients, and these drugs are
associated with dose-dependent adverse cardiorespiratory
effects. A decrease in blood pressure is not uncommon and is
associated with a decrease in cardiac output.7 The safety of
general anesthesia would, therefore, be improved if a technique
were available to decrease the inhalation anesthetic needed for
general anesthesia.7 The MAC of an inhalant anesthetic corre-
sponds to the amount of drug necessary for surgical procedures.
The MAC is the minimum alveolar concentration at steady
state that will prevent gross purposeful movement in 50% of
patients when subjected to a noxious stimulus such as surgical
manipulation.5-7 The MAC can be influenced by a number of
factors including but not limited to, age, temperature, and con-
current disease. Great care was taken in the present study to
minimize any influences that could affect the MAC results.
Dogs were placed on a tabletop heating pad with a forced air
warmer to keep temperature constant; the dogs were of the
same age and all were in good health. Additionally, it has been
shown that the MAC of an inhalant can vary over time in the
same individual and with circadian rhythm.21 Care was taken to
minimize these effects by anesthetizing the dogs in 2 succes-
sive weeks at approximately the same time each day. The dura-
tion of anesthesia was similar in all dogs for all treatments.
Regardless, MAC is not influenced by the duration of
anesthesia.6
The objective of the present study was to evaluate the
effects of buprenorphine with bupivacaine (MACbupbup) and
bupivacaine alone (MACbupiv), on the anesthetic require-
ment of isoflurane in dogs. Both treatments demonstrated
approximately a 20% MAC reduction (22% MACbupiv,
19% MACbupbup). Use of a local anesthetic alone has
Journal of Veterinary Dentistry 33(2)
previously been shown to reduce the MAC of dogs receiving
a noxious stimulus designed to simulate oral pain associated
with maxillary canine tooth extraction in dogs.16 Results of
the current study indicated prolonged activity of the regional
anesthetic block for both treatment groups; however, the total
number of dogs demonstrating a MAC reduction and the over-
all degree of MAC reduction for the MACbupbup group was
greater. The clinical ramifications of these reductions require
further investigations but may offer both improved analgesia
during anesthetic recovery following a painful treatment and
multimodal pain management as the patient is transitioned to
oral pain medications following metabolism of systemically
dosed predications.
The authors had expected that the MACbupbup would
remain below baseline significantly longer than the MACbu-
piv group; however, failure to prove this hypothesis may be
rooted in several issues. First, the current study was based on
a model of acute dental pain in research animals. Without
chronic noxious stimulation analogous to conditions such as
chronically exposed pulp chambers or feline chronic gingi-
vostomatitis, there may have been inadequate upregulation of
mu receptors in the periphery for the opioid to exert an
effect. Statistical evaluation was performed to determine
whether the order of the 2 treatment groups demonstrated
any significant difference in the impact of use of buprenor-
phine in dogs receiving the MACbupbup treatment that had
previously received multiple days of stimulation while being
treated with MACbupiv treatment. No difference was found.
Second, the small sample size of 8 dogs was insufficient to
demonstrate significance with these results. Estimated group
sizes of 40 dogs in each treatment group would be necessary
to demonstrate a difference between both treatments. Third,
human studies investigating the effect of opioids mixed into
local anesthetic blocks report results from the actual clinical
patient’s postoperative perception of pain. Considering the
profound challenge to accurately assess the degree of discom-
fort a dog feels, more invasive testing measures such as
dental dolorimetry are required and subsequently may be
overestimating perceived pain.
Upregulation of mu receptors has been shown to occur in
states of chronic noxious stimulation. Periodontal disease has
been shown to occur commonly in the veterinary population and
is likely chronic in nature for most veterinary dental patients.
Acute injuries including concussive injury resulting in pulpitis,
tooth fracture, jaw fracture, and acute soft tissue trauma are all
conditions less likely to be associated with central or peripheral
sensitization. A high prevalence of existing dental trauma has
been reported in veterinary patients with injury to the head or
face22,23; however, the duration of presence of those injuries is
unknown. Addition of opioid administered locally in conjunc-
tion with local anesthetic may have particular benefit to patients
demonstrating states of chronic inflammation or disease since
the opioid can bind to the peripheral mu receptors and extend the
duration of action as reported in humans.17,24 Further investiga-
tion is necessary to determine whether this is similar in veter-
inary patients.
Snyder et al
It is unknown what impact serial stimulation has on the hard
and soft tissues. No difference in MAC reduction was noted
between dogs that received buprenorphine during phase 1 of
treatment or phase 2. A larger sample size for each group would
be necessary to determine whether electrical stimulation alone
would be enough to upregulate peripheral mu receptors. A
MAC reduction of 20% or greater is commonly accepted as
clinically significant7; however, the impact of lesser reductions
on individual patients is unknown and likely patient specific.
There are no previous studies evaluating the duration of activ-
ity for bupivacaine (extra-label local anesthetic use in animals)
when used for regional anesthesia in dental procedures in dogs.
Results of this study demonstrate the greatest reduction in
MAC of the MACbupiv group during testing on day one, sig-
nifying the greatest potential effect. The MAC reduction of
MACbupbup group reflected a similar decrease in MAC on
day 1 and maintained a similar decrease on days 3 to 5 of the
dogs remaining in the study indicating a prolonged effect in
dogs receiving the MACbupbup treatment.
The heart rate and mean arterial blood pressure were mea-
sured throughout anesthesia, both before application of noxious
stimulation and immediately following application. The results
were reported at the lowest end-tidal isoflurane concentration
where the noxious stimulus did not produce gross purposeful
movement. We found that there was a slight decrease in beats
per min (bpm) in the MACbupbup group compared to the
MACbupiv group of 7.8 bpm (P ¼ .073). This could be due
to the slight bradycardic effects of the opioid in the MAC-
bupbup block. We also found that the MACbupbup had a
significant linear decrease in heart rate of 3.0 bpm per day
(P ¼ .034). The MAP for the MACbupiv group decreased per
day by 5.2 mm Hg while the MACbupbup group decreased
only -0.2 mm Hg per day, causing a significant difference
between groups for MAP over time (P ¼ .006). The authors
propose no reasons for the heart rate decrease per day or the
differences in MAP between groups other than individual
variation on individual days.
In conclusion, the addition of buprenorphine to regional
bupivacaine anesthesia via an infraorbital nerve block did not
extend the duration of nerve blockade in a statistically signif-
icant manner compared to regional bupivacaine anesthesia
alone as measured by repeated MAC determinations. How-
ever, both treatments decreased the MAC of isoflurane by
22% in the MACbupiv treatment group and by 19% in the
MACbupbup treatment group. Regional anesthesia using
bupivacaine alone or bupivacaine plus buprenorphine via an
infraorbital nerve block significantly reduced the isoflurane
MAC in dogs without adversely affecting cardiovascular
parameters or causing observable adverse effects. Addition-
ally, bupivacaine appears to have a duration of action longer
than previously reported. Results of this study demonstrate
that the addition of buprenorphrine may enhance the analgesic
duration of effect for bupivacaine regional nerve blocks. Fur-
ther studies are necessary to determine the exact effects of the
addition of and appropriate dose of buprenorphine added to
regional blocks in veterinary patients and effects of the
95
addition of buprenorphine to regional blocks in patients with
chronic pain.
Notes
1. Lactated Ringer’s Solution; Hospira Inc, Lake Forrest, Illinois.
2. Propofol; Ben Venue Laboratories, Inc, Bedford, Ohio.
3. Isoflo; Abbot, North Chicago, Illinois.
4. Cardiocap/5; Datex Ohmeda, Louisville, Colorado.
5. GRASS SD9 Square Pulse Stimulator; Astro-Med Inc, West War-
wick, Rhode Island.
6. 0.5% Marcaine; Hospira Inc, Lake Forrest, Illinois.
7. Buprenex; Reckitt Benckiser Pharmaceuticals, Richmond,
Virginia.
Authors’ Note
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the NIH.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: This study
was supported by a grant provided by the Academy of Veterinary
Dentistry. The project described was supported by the Clinical and
Translational Science Award (CTSA) program, through the NIH
National Center for Advancing Translational Sciences (NCATS),
grant UL1TR000427.
References
1. Muir WW III, Bednarski L, Bednarski R. Thiamylal – and
halothane-sparing effects of diazepam in dogs. J Vet Pharmacol
Ther. 1991;14(1):46-50.
2. Tranquilli WJ, Thurmon JC, Corbin JE, et al. Halothane-sparing
effect of xylazine in dogs and subsequent reversal with tolazoline.
J Vet Pharmacol Ther. 1984;7(1):23-28.
3. Steffey EP, Baggot JD, Eisele JH, et al. Morphine-isoflurane
interactions in dogs, swine, and rhesus monkeys. J Vet Pharmacol
Ther. 1994;17(3):202-210.
4. Muir WW III, Weise AJ, March PA. Effects of morphine, lido-
caine, ketamine, and morphine-lidocaine-ketamine drug combi-
nation on the minimum alveolar concentration in dogs
anesthetized with isoflurane. Am J Vet Res. 2003;64(9):
1155-1160.
5. Quasha AL, Eger EI, Tinker JH. Determination and application of
MAC. Anesthesiology. 1980;53(4):315-334.
6. Eger EI, Saidman LJ, Brandstater B. Minimum alveolar concen-
tration: a standard of anesthetic potency. Anesthesiology. 1965;
26(6):756-763.
7. Jeong SM. Effects of electroacupuncture on minimum alveolar
concentration of isoflurane and cardiovascular system in isoflur-
ane anesthetized dogs. J Vet Sci. 2002;3(3):193-201.
8. Zbinden AM, Maggiorini M, Petersen-Felix S, Lauber R, Thom-
son DA, Minder CE. Anesthetic depth defined using multiple
96
noxious stimuli during isoflurane/oxygen anesthesia. I. Motor
reactions. Anesthesiology. 1994;80(2):253-260.
9. Culp LB, Skarda RT, Muir WW III. Comparisons of the effects of
acupuncture, electroacupuncture, and transcutaneous cranial elec-
trical stimulation on the minimum alveolar concentration of iso-
flurane in dogs. Am J Vet Res. 2005;66(8):1364-1370.
10. Mitchell CL. A comparison of drug effects upon the jaw jerk
response to electrical stimulation of the tooth pulp in dogs and
cats. J Pharmocol Exp Ther. 1964;146:1-6.
11. Brunson DB, Collier MA, Scott EA, Majors LJ. Dental dolorime-
try for the evaluation of an analgesic agent in the horse. Am J Vet
Res. 1987;48(7):1082-1086.
12. Brown DC, Bernier N, Shofer F, Steinberg SA, Perkowski SZ.
Use of noninvasive dental dolorimetry to evaluate analgesic
effects of intravenous and intrathecal administration of morphine
in anesthetized dogs. Am J Vet Res. 2002;63(10):1349-1353.
13. Brown DC, Bernier N, Shofer F, Steinberg SA, Perkowski SZ.
Effect of intrathecal and intravenous administration of oxytocin
on amplitude of the reflex-evoked muscle action potential after
electrical stimulation of the tooth pulp in anesthetized dogs. Am J
Vet Res. 2002;63(10):1354-1358.
14. Gross ME, Pope ER, O’Brien, et al. Regional anesthesia of the
infraorbital and inferior alveolar nerves during noninvasive tooth
pulp stimulation in halothane-anesthetized dogs. J Am Vet Med
Assoc. 1997;211(11):1403-1405.
15. Gross ME, Pope ER, Jarboe JM, O’Brien DP, Dodam JR, Polkow-
Haight J. Regional anesthesia of the infraorbital and inferior
alveolar nerves during noninvasive tooth pulp stimulation in
halothane-anesthetized cats. Am J Vet Res. 2000;61(10):
1245-1247.
16. Snyder CJ, Snyder LBC. Effects of mepivacaine in an infraor-
bital nerve block on minimum alveolar concentration of
Journal of Veterinary Dentistry 33(2)
isoflurane in clinically normal anesthetized dogs undergoing a
modified form of dental dolorimetry. J Am Vet Med Assoc. 2013;
242(2):199-204.
17. Modi M, Rastogi S, Kumar A. Buprenorphine with bupivacaine
for intraoral nerve blocks to provide postoperative analgesia in
outpatients after minor oral surgery. J Oral Maxillofac Surg.
2009;67(12):2571-2576.
18. Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A. Peripheral
opioid receptors mediating antinociception in inflammation. Evi-
dence for involvement of mu, delta and kappa receptors. J Phar-
macol Exp Ther. 1989;248(3):1269-1275.
19. Gao F, Waters B, Seager J, Dowling C, Vickers MD. Com-
parison of bupivacaine plus buprenorphine with bupivacaine
alone by caudal blockade for post-operative pain relief after
hip and knee arthroplasty. Eur J Anaesthesiol. 1995;12(5):
471-476.
20. Hofmeister EH, Brainard BM, Sams LM, Allman DA, Cruse AM.
Evaluation of induction characteristics and hypnotic potency of
isoflurane and sevoflurane in healthy dogs. Am J Vet Res. 2008;
69(4):451-456.
21. Eger EI. MAC. In: Eger EI, ed. Anesthetic Uptake and Action.
Baltimore, MD: Williams & Wilkins Co; 1974:1-25.
22. Bonner SE, Reiter AM, Lewis JR. Orofacial manifestations of
high-rise syndrome in cats: a retrospective study of 84 cats. J Vet
Dent. 2012;29(1):10-18.
23. Soukup JW, Mulherin BL, Snyder CJ. Prevalence and nature of
dentoalveolar injuries among patients with maxillofacial frac-
tures. J Sm Anim Pract. 2013;54(1):9-14.
24. Candido KD, Franco CD, Khan MA, Winnie AP, Raja DS. Bupre-
norphine added to the local anesthetic for brachial plexus block to
provide postoperative analgesia in outpatients. Reg Anesth Pain
Mgmt. 2001;26(4):352-356.